Molecular imaging of activated matrix metalloproteinases in vascular remodeling.
BACKGROUND
Matrix metalloproteinase (MMP) activation plays a key role in vascular remodeling. RP782 is a novel indium (111)In-labeled tracer with specificity for activated MMPs. We hypothesized that RP782 can detect injury-induced vascular remodeling in vivo.


RESULTS
Left common carotid artery injury was induced with a guidewire in apolipoprotein E(-/-) mice. Sham surgery was performed on the contralateral artery, which served as control for imaging experiments. Carotid wire injury led to significant hyperplasia and expansive remodeling over a period of 4 weeks. MMP activity, detected by in situ zymography, increased in response to injury and was maximal by 3 to 4 weeks after injury. RP782 (11.1 MBq) was injected intravenously into apolipoprotein E(-/-) mice at 1, 2, 3, and 4 weeks after left carotid injury. MicroSPECT imaging was performed at 2 hours and was followed by CT angiography to localize the carotid arteries. In vivo images revealed focal uptake of RP782 in the injured carotid artery at 2, 3, and 4 weeks. Increased tracer uptake in the injured artery was confirmed by quantitative autoradiography. Pretreatment with 50-fold excess nonlabeled tracer significantly reduced RP782 uptake in injured carotids, thus demonstrating uptake specificity. Weekly changes in the vessel-wall area closely paralleled and correlated with RP782 uptake (Spearman r=0.95, P=0.001).


CONCLUSIONS
Injury-induced MMP activation in the vessel wall can be detected by RP782 microSPECT/CT imaging in vivo. RP782 uptake tracks the hyperplastic process in vascular remodeling and provides an opportunity to track the remodeling process in vivo.
Zhang
Jiasheng
J
Raymond and Beverly Sackler Cardiovascular Molecular Imaging Laboratory, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Conn., USA.
Nie
Lei
L
Razavian
Mahmoud
M
Ahmed
Masood
M
Dobrucki
Lawrence W
LW
Asadi
Abolfazl
A
Edwards
D Scott
DS
Azure
Michael
M
Sinusas
Albert J
AJ
Sadeghi
Mehran M
MM
D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001345:Autoradiography; D020212:Carotid Artery Injuries / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D017536:Carotid Artery, Common / Q000000981:diagnostic imaging* / Q000201:enzymology* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005455:Fluorescent Antibody Technique; D007204:Indium; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D012680:Sensitivity and Specificity; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*
D001057:Apolipoproteins E; D007204:Indium; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse